We are investigating the molecular mechanisms mediating monocytotropic/primary (MT) and T cell line tropic (TCT) virus binding and entry into CD4+ cells. The b-chemokine, RANTES, blocks MT virus infection by competitive inhibition at the coreceptor level by preventing a gp120 V3-region dependent post-binding membrane fusion step. We and others have recently confirmed the role of CKR5 in MT infection by transfection of the specific gene encoding CKR5 into Jurkat cells and into CD4 bearing 293 fibroblast cells. In addition, we have extended our studies on the role of cell surface dipeptidase, CD26, in the infection of MT viruses. Expression of CD26 enhances MT virus entry and fusion by regulating the production and activity of antiviral chemokines. Our results linking CD26 to chemokines may explain why CD26 positive cells are lost from the circulation in HIV infected patients and could lead to new HIV-1 therapeutic and prevention strategies. We have continued our studies on the role of cell surface heparan sulfate proteoglycans (HSPG) as an accessory molecule in mediating virus attachment and infection. T cell line tropic viruses are highly dependent on positive amino acids in the envelope gp120 V3 region for binding HSPGs and for interactions with the recently defined LESTR/Fusin coreceptor. In contrast, MT viruses are not blocked by sulfated compounds and are actually enhanced by soluble heparin or heparitinase. Effects of heparin and heparitinase on MT virus infection are mediated in part by the ability of heparin and HSPG to bind inhibitory chemokines.